The myelin-associated glycoprotein (MAG) is selectively localized in the periaxonal part of PNS and CNS myelin sheaths where it is likely to be involved in glia-axon interactions. This function was supported by recent immunocytochemical studies in Quaking mice showing a strict correlation between the presence of MAG and the maintenance of a 12-14 nm periaxonal space as well as a Schwann cell periaxonal cytoplasmic collar. Higher than normal apparent Mr's were demonstrated for MAG in the PNS of Trembler mice and in the CNS and PNS of Quaking mice suggesting that the abnormal MAG may contribute to the pathology in these hypomyelinating mutants. A panel of monoclonal antibodies reacting with polypeptide and carbohydrate sites on the MAG molecule has been produced by hybridoma techniques in mice. Monoclonal IgM produced in patients with paraproteinemia associated with peripheral neuropathy reacts with a carbohydrate epitope that is in human MAG as well as a ganglioside and other glycoconjugates of human peripheral nerve. HNK-1, a monoclonal antibody recognizing a surface determinant on a subset of human lymphocytes with natural killer and suppressor functions, binds to the same or a very similar carbohydrate epitope. This shared carbohydrate antigen between human lymphocytes and several glycoconjugates including MAG of the nervous system appears to be highly immunogenic and may be of significance with regard to demyelinating diseases. Other patients with gammopathy and neuropathy have been identified in which the paraprotein binds to different gangliosides of peripheral nerve. [3H]Thymidine incorporation studies show that some multiple sclerosis patients have peripheral blood lymphocytes sensitized to MAG and other myelin proteins. A neutral protease that converts MAG to a lower molecular weight derivative, dMAG, and degrades myelin basic protein is elevated in myelin isolated from multiple sclerosis brains, suggesting that it may function in autodegradation of myelin in demyelinating diseases.